Regulation of pancreas development by hedgehog signaling

Development ◽  
2000 ◽  
Vol 127 (22) ◽  
pp. 4905-4913 ◽  
Author(s):  
M. Hebrok ◽  
S.K. Kim ◽  
B. St Jacques ◽  
A.P. McMahon ◽  
D.A. Melton
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Signaling Molecules ◽  
Pancreatic Tissue ◽  
Negative Regulator ◽  
Pancreas Development ◽  
Fourfold Increase ◽  
Embryonic Pancreas ◽  
Patched 1 ◽  
Targeted Inactivation

Pancreas organogenesis is regulated by the interaction of distinct signaling pathways that promote or restrict morphogenesis and cell differentiation. Previous work has shown that activin, a TGF(beta+) signaling molecule, permits pancreas development by repressing expression of Sonic hedgehog (Shh), a member of the hedgehog family of signaling molecules that antagonize pancreas development. Here we show that Indian hedgehog (Ihh), another hedgehog family member, and Patched 1 (Ptc1), a receptor and negative regulator of hedgehog activity, are expressed in pancreatic tissue. Targeted inactivation of Ihh in mice allows ectopic branching of ventral pancreatic tissue resulting in an annulus that encircles the duodenum, a phenotype frequently observed in humans suffering from a rare disorder known as annular pancreas. Shh(−)(/)(−) and Shh(−)(/)(−) Ihh(+/)(−) mutants have a threefold increase in pancreas mass, and a fourfold increase in pancreatic endocrine cell numbers. In contrast, mutations in Ptc1 reduce pancreas gene expression and impair glucose homeostasis. Thus, islet cell, pancreatic mass and pancreatic morphogenesis are regulated by hedgehog signaling molecules expressed within and adjacent to the embryonic pancreas. Defects in hedgehog signaling may lead to congenital pancreatic malformations and glucose intolerance.

scholarly journals Unique functions of Sonic hedgehog signaling during external genitalia development

Development ◽  
2001 ◽  
Vol 128 (21) ◽  
pp. 4241-4250 ◽  
Author(s):  
Ryuma Haraguchi ◽  
Rong Mo ◽  
Chi-chung Hui ◽  
Jun Motoyama ◽  
Shigeru Makino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
External Genitalia ◽  
Sonic Hedgehog Signaling ◽  
Urethral Plate ◽  
Morphogenetic Protein ◽  
Fibroblast Growth Factor 10 ◽  
Dramatic Shift ◽  
Patched 1

Coordinated growth and differentiation of external genitalia generates a proximodistally elongated structure suitable for copulation and efficient fertilization. The differentiation of external genitalia incorporates a unique process, i.e. the formation of the urethral plate and the urethral tube. Despite significant progress in molecular embryology, few attempts have been made to elucidate the molecular developmental processes for external genitalia. The sonic hedgehog (Shh) gene and its signaling genes have been found to be dynamically expressed during murine external genitalia development. Functional analysis by organ culture revealed that Shh could regulate mesenchymally expressed genes, patched 1 (Ptch1), bone morphogenetic protein 4 (Bmp4), Hoxd13 and fibroblast growth factor 10 (Fgf10), in the anlage: the genital tubercle (GT). Activities of Shh for both GT outgrowth and differentiation were also demonstrated. Shh–/– mice displayed complete GT agenesis, which is compatible with such observations. Furthermore, the regulation of apoptosis during GT formation was revealed for the first time. Increased cell death and reduced cell proliferation of the Shh–/– mice GT were shown. A search for alterations of Shh downstream gene expression identified a dramatic shift of Bmp4 gene expression from the mesenchyme to the epithelium of the Shh mutant before GT outgrowth. Regulation of mesenchymal Fgf10 gene expression by the epithelial Shh was indicated during late GT development. These results suggest a dual mode of Shh function, first by the regulation of initiating GT outgrowth, and second, by subsequent GT differentiation.

scholarly journals Lateral cerebellum is preferentially sensitive to high sonic hedgehog signaling and medulloblastoma formation

2018 ◽  
Vol 115 (13) ◽  
pp. 3392-3397 ◽  
Author(s):  
I-Li Tan ◽  
Alexandre Wojcinski ◽  
Harikrishna Rallapalli ◽  
Zhimin Lao ◽  
Reeti M. Sanghrajka ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Of Origin ◽  
Sonic Hedgehog Signaling ◽  
Patched 1 ◽  
High Level ◽  
Opposing Effects ◽  
Developing Cerebellum

The main cell of origin of the Sonic hedgehog (SHH) subgroup of medulloblastoma (MB) is granule cell precursors (GCPs), a SHH-dependent transient amplifying population in the developing cerebellum. SHH-MBs can be further subdivided based on molecular and clinical parameters, as well as location because SHH-MBs occur preferentially in the lateral cerebellum (hemispheres). Our analysis of adult patient data suggests that tumors with Smoothened (SMO) mutations form more specifically in the hemispheres than those with Patched 1 (PTCH1) mutations. Using sporadic mouse models of SHH-MB with the two mutations commonly seen in adult MB, constitutive activation of Smo (SmoM2) or loss-of-Ptch1, we found that regardless of timing of induction or type of mutation, tumors developed primarily in the hemispheres, with SmoM2-mutants indeed showing a stronger specificity. We further uncovered that GCPs in the hemispheres are more susceptible to high-level SHH signaling compared with GCPs in the medial cerebellum (vermis), as more SmoM2 or Ptch1-mutant hemisphere cells remain undifferentiated and show increased tumorigenicity when transplanted. Finally, we identified location-specific GCP gene-expression profiles, and found that deletion of the genes most highly expressed in the hemispheres (Nr2f2) or vermis (Engrailed1) showed opposing effects on GCP differentiation. Our studies thus provide insights into intrinsic differences within GCPs that impact on SHH-MB progression.

scholarly journals Antiandrogen Exposure in Utero Disrupts Expression of Desert Hedgehog and Insulin-Like Factor 3 in the Developing Fetal Rat Testis

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 445-451 ◽  
Author(s):  
Leon J. S. Brokken ◽  
Annika Adamsson ◽  
Jorma Paranko ◽  
Jorma Toppari
Keyword(s):  
Gene Expression ◽  
Sonic Hedgehog ◽  
Sexual Differentiation ◽  
Hedgehog Signaling ◽  
In Utero ◽  
Testicular Development ◽  
Expression Levels ◽  
Desert Hedgehog ◽  
Patched 1 ◽  
Gene Expression Levels

Testicular development is an androgen-dependent process, and fetal exposure to antiandrogens disrupts male sexual differentiation. A variety of testicular disorders may result from impaired development of fetal Leydig and Sertoli cells. We hypothesized that antiandrogenic exposure during fetal development interferes with desert hedgehog (Dhh) signaling in the testis and results in impaired Leydig cell differentiation. Fetal rats were exposed in utero to the antiandrogen flutamide from 10.5 d post conception (dpc) until they were killed or delivery. Fetal testes were isolated at different time points during gestation and gene expression levels of Dhh, patched-1 (Ptc1), steroidogenic factor 1 (Sf1), cytochrome P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (Hsd3b1), and insulin-like factor 3 (Insl3) were analyzed. To study direct effects of hedgehog signaling on testicular development, testes from 14.5 dpc fetuses were cultured for 3 d in the presence of cyclopamine, sonic hedgehog, or vehicle, and gene expression levels and testosterone secretion were analyzed. Organ cultures were also analyzed histologically, and cleaved-caspase 3 immunohistochemistry was performed to assess apoptosis. In utero exposure to flutamide decreased expression levels of Dhh, Ptc1, Sf1, P450scc, Hsd3b1, and Insl3, particularly from 17.5 dpc onward. Inhibition of hedgehog signaling in testis cultures resulted in similar effects on gene expression levels. Apoptosis in Wolffian ducts was increased by cyclopamine compared with sonic hedgehog- or vehicle-treated cultures. We conclude that exposure to the antiandrogen flutamide interferes with Dhh signaling resulting in an impaired differentiation of the fetal Leydig cells and subsequently leading to abnormal testicular development and sexual differentiation. Antiandrogenic exposure of rat fetuses in utero affects genes that are involved in sexual differentiation of the testis and suppresses sexual maturation.

scholarly journals Patched 1 reduces the accessibility of cholesterol in the outer leaflet of membranes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Maia Kinnebrew ◽  
Giovanni Luchetti ◽  
Ria Sircar ◽  
Sara Frigui ◽  
Lucrezia Vittoria Viti ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Live Cells ◽  
Transport Activity ◽  
Outer Leaflet ◽  
Cholesterol Levels ◽  
Patched 1 ◽  
Potassium Gradient ◽  
Kinetics Of

A long-standing mystery in vertebrate Hedgehog signaling is how Patched 1 (PTCH1), the receptor for Hedgehog ligands, inhibits the activity of Smoothened, the protein that transmits the signal across the membrane. We previously proposed (Kinnebrew et al., 2019) that PTCH1 inhibits Smoothened by depleting accessible cholesterol from the ciliary membrane. To directly test the effect of PTCH1 on accessible cholesterol, we measured the transport activity of PTCH1 using an imaging-based assay to follow the kinetics of cholesterol extraction from the plasma membrane of live cells by methyl-β-cyclodextrin. PTCH1 depletes accessible cholesterol in the outer leaflet of the membrane in a manner regulated by its ligand Sonic Hedgehog and the transmembrane potassium gradient. We propose that PTCH1 moves cholesterol from the outer to the inner leaflet of the membrane in exchange for potassium ion export. Our results show that proteins can change accessible cholesterol levels in membranes to regulate signaling reaction.

Expression of Sonic hedgehog signaling molecules in normal, hyperplastic and carcinomatous endometrium

2009 ◽  
Vol 59 (5) ◽  
pp. 279-287 ◽  
Author(s):  
Kyung Hee Kim ◽  
Jin Man Kim ◽  
Yoon-La Choi ◽  
Young Kee Shin ◽  
Ho-chang Lee ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Signaling Molecules ◽  
Sonic Hedgehog Signaling

scholarly journals Spatiotemporal expression of sonic hedgehog signaling molecules in the embryonic mesencephalic dopaminergic neurons

2020 ◽  
Author(s):  
Manal T Hussein ◽  
Abdelraheim Attaai ◽  
Gamal Kamel ◽  
Doaa Mokhtar
Keyword(s):  
Primary Culture ◽  
Cell Line ◽  
Sonic Hedgehog ◽  
Dopaminergic Neurons ◽  
Hedgehog Signaling ◽  
Signaling Molecules ◽  
Main Role ◽  
Shh Signaling ◽  
Mn9d Cells

Abstract Background Midbrain dopaminergic neurons (mDA) play an important role in controlling the voluntary motor movement, reward behavior and emotion-based behavior. Differentiation of mDA neurons from progenitors depends on a number of secreted proteins, such as sonic hedgehog (SHH), and transcription factors. Different groups from mDA neurons arise from the varied patterns of SHH expression during development. The present study attempted to elucidate 1) the possible role(s) of some SHH signaling components (Ptch1, Gli1, Gli2 and Gli3) in the spatiotemporal development of mDA neurons along the rostrocaudal axis of the midbrain and their possible roles in differentiation (E12, E14) and survival of mDA neurons (E18); 2) the main role of Boc (bioregional Cdon-binding protein), and Gas1 (growth arrest-specific 1) as novel accessory receptors for the SHH in the development of mDA neurons 3) the significance of using the primary culture and/or the dopaminergic cell line (MN9D) for studying the development of mDA neurons. Results Mice embryos from embryonic day (E)12 were used for in situ hybridization and immunohistochemistry. The primary culture and cell line MN9D were used for in vitro investigation. At E12 and E14, but not E18, only Ptch1 and Gli1 were expressed in ventrolateral midbrain domains. All examined SHH signaling molecules were not detected in mDA area. Whereas, in MN9D cells, many SHH signaling molecules were expressed and co-localized with dopaminergic marker; tyrosine hydroxylase (TH), and their expression were upregulated with SHH treatment of the MN9D cells. Conclusion These results suggest that mDA neurons differentiation and survival are independent of SHH. In addition, MN9D cell line is not the ideal in vitro model for investigating the differentiation of mesencephalic dopaminergic neurons, and hence, the ventral midbrain primary culture might be favored over MN9D line.

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